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Kagemoto K, Okamoto K, Okada Y, sei M, Fujimoto S, Yagi M, Mitsuhashi T, Ueda H, Yoshimoto T, Kashihara T, Kawaguchi T, Kida Y, Mitsui Y, Kawano Y, Sogabe M, Miyamoto H, Sato Y, Muguruma N, Takayama T. Clinicopathological evaluation of the efficacy of endoscopic treatment for sessile serrated lesions comparing endoscopic mucosal resection, cold snare polypectomy, and underwater endoscopic mucosal resection. DEN OPEN 2025; 5:e70051. [PMID: 39758158 PMCID: PMC11695825 DOI: 10.1002/deo2.70051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 11/18/2024] [Accepted: 12/16/2024] [Indexed: 01/07/2025]
Abstract
OBJECTIVES Recently, various endoscopic treatments for colorectal polyps have been reported, including cold snare polypectomy (CSP) and underwater endoscopic mucosal resection (UEMR), in addition to EMR. However, a precise treatment strategy for sessile serrated lesions (SSL) has not been established. In this study, we analyzed the clinicopathological features of SSL resected by EMR, CSP, and UEMR to determine the most suitable treatment for SSL. METHODS A total of 92 SSL resected via EMR (n = 11), CSP (n = 36), and UEMR (n = 45) were retrospectively enrolled between February 2021 and October 2022. To evaluate pathological findings, we examined SSL samples, which were stretched before formalin fixation and sectioned at 2-mm intervals. Primary outcomes were the R0 resection rate and thickness of submucosal (SM) tissue specimens for each treatment. In addition, we evaluated SSL with dysplasia (SSLD) and the inverted growth pattern which may affect the vertical margin. RESULTS The R0 resection rate significantly differed among the three groups (EMR, 73%; CSP, 42%; UEMR, 87%, p = 0.001). The median thickness of SM tissue resected by CSP (0 µm) was significantly less than that by EMR (362 µm) and UEMR (325 µm; p < 0.001). All four SSLDs were diagnosed endoscopically. Five SSLs with inverted growth patterns were pathologically diagnosed. Of these, two SSLs with inverted growth patterns could not be diagnosed endoscopically. CONCLUSIONS UEMR is considered to be a suitable treatment option for SSL. CSP results were pathologically insufficient. Therefore, surveillance to evaluate local recurrence is important, and the results of further multicenter prospective studies should be referred.
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Affiliation(s)
- Kaizo Kagemoto
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Koichi Okamoto
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Yasuyuki Okada
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Motoko sei
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Shota Fujimoto
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Mai Yagi
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Takeshi Mitsuhashi
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Hiroyuki Ueda
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Takanori Yoshimoto
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Takanori Kashihara
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Tomoyuki Kawaguchi
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Yoshifumi Kida
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Yasuhiro Mitsui
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Yutaka Kawano
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Masahiro Sogabe
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Yasushi Sato
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Naoki Muguruma
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
- Department of GastroenterologyTakamatsu Municipal HospitalKagawaJapan
| | - Tetsuji Takayama
- Department of Gastroenterology and OncologyInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
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Hajebi Khaniki S, Shokoohi F. Data-Driven Identification of Early Cancer-Associated Genes via Penalized Trans-Dimensional Hidden Markov Models. Biomolecules 2025; 15:294. [PMID: 40001597 PMCID: PMC11853217 DOI: 10.3390/biom15020294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 02/13/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Colorectal cancer (CRC) is a significant worldwide health problem due to its high prevalence, mortality rates, and frequent diagnosis at advanced stages. While diagnostic and therapeutic approaches have evolved, the underlying mechanisms driving CRC initiation and progression are not yet fully understood. Early detection is critical for improving patient survival, as initial cancer stages often exhibit epigenetic changes-such as DNA methylation-that regulate gene expression and tumor progression. Identifying DNA methylation patterns and key survival-related genes in CRC could thus enhance diagnostic accuracy and extend patient lifespans. In this study, we apply two of our recently developed methods for identifying differential methylation and analyzing survival using a sparse, finite mixture of accelerated failure time regression models, focusing on key genes and pathways in CRC datasets. Our approach outperforms two other leading methods, yielding robust findings and identifying novel differentially methylated cytosines. We found that CRC patient survival time follows a two-component mixture regression model, where genes CDH11, EPB41L3, and DOCK2 are active in the more aggressive form of CRC, whereas TMEM215, PPP1R14A, GPR158, and NAPSB are active in the less aggressive form.
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Affiliation(s)
- Saeedeh Hajebi Khaniki
- Department of Biostatistics, School of Health, Mashhad University of Medical Sciences, Mashhad 9137673119, Iran;
| | - Farhad Shokoohi
- Department of Mathematical Sciences, University of Nevada Las Vegas, Las Vegas, NV 89154, USA
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3
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Sarangi J, Das P, Ahmad A, Sulaiman M, Ghosh S, Gupta B, Panwar R, Pal S, Yadav R, Ahuja V, Sen S, Upadhyay AD, Dash NR, Sharma A, Gupta SD. Methylation study of tumor suppressor genes in human aberrant crypt foci, colorectal carcinomas, and normal colon. J Cancer Res Ther 2024; 20:268-274. [PMID: 38554332 DOI: 10.4103/jcrt.jcrt_1573_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 09/22/2022] [Indexed: 04/01/2024]
Abstract
BACKGROUND Aberrant crypt foci (ACF) are the earliest preneoplastic lesions in human colon, identifiable on chromoendoscopic screening. Our objective was to evaluate the %methylation of APC, CDKN2A, MLH1, RASSF1, MGMT, and WIF1 tumor suppressor genes (TSG) in ACF, corresponding colorectal carcinomas (CRC), and normal colonic mucosal controls. METHODS In this study, macroscopically normal-appearing mucosal flaps were sampled 5-10 cm away from the tumor mass from 302 fresh colectomy specimens to identify ACF-like lesions. Thirty-five cases with multiple ACFs were selected (n 35) as the main study group, with corresponding sections from CRC (n 35) as disease controls, and mucosal tissue blocks from 20 colectomy specimens (normal controls), operated for non-neoplastic pathologies. Genomic DNA was extracted, and methylation-specific polymerase chain reaction (PCR) was performed on a customized methylation array model. %Methylation data were compared among the groups and with clinicopathological parameters. Selected target mRNA and protein expression studies were performed. RESULTS %Methylation of TSGs in ACF was intermediate between normal colon and CRC, although a statistically significant difference was observed only for the WIF1 gene (P < 0.01). Also, there was increased nuclear β-catenin expression and upregulation of CD44-positive cancer-stem cells in ACF and CRCs than in controls. Right-sided ACFs and dysplastic ACFs had a higher %methylation of CDKN2A (P < 0.01), whereas hyperplastic ACFs had a higher %methylation of RASSF1 (P 0.04). The topographic characteristics of ACFs did not correlate with TSG %methylation. CONCLUSIONS Early epigenetic methylation of WIF1 gene is one of the mechanisms for ACF development in human colon.
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Affiliation(s)
- Jayati Sarangi
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Aijaz Ahmad
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Mohamed Sulaiman
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Shouriyo Ghosh
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Brijnandan Gupta
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Rajesh Panwar
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Sujoy Pal
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Rajni Yadav
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Vineet Ahuja
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Sudip Sen
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Asish D Upadhyay
- Department of Biostatistics and, All India Institute of Medical Sciences, New Delhi, India
| | - Nihar R Dash
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Atul Sharma
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Siddhartha D Gupta
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
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El Kamouh M, Brionne A, Sayyari A, Laurent A, Labbé C. Cryopreservation effect on DNA methylation profile in rainbow trout spermatozoa. Sci Rep 2023; 13:19029. [PMID: 37923780 PMCID: PMC10624875 DOI: 10.1038/s41598-023-44803-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 10/12/2023] [Indexed: 11/06/2023] Open
Abstract
Spermatozoa are the cells that are most commonly used for cryopreservation of valuable genetic resources in aquaculture. It is known that fish spermatozoa transmit to the embryo not only their genetic but also their epigenetic profile, especially DNA methylation. Therefore, any alteration of the DNA methylation profile in spermatozoa induces the risk of transmitting epigenetic alterations to the offspring. The aim of this study was to assess the effect of cryopreservation on DNA methylation in rainbow trout spermatozoa. To trigger variable cellular response after freezing-thawing, spermatozoa from mature males were cryopreserved with dimethyl sulfoxide, methanol or glycerol as cryoprotectant. We observed that dimethyl sulfoxide was the best to preserve thawed spermatozoa functions. Methanol only slightly preserved all the cellular parameters, while glycerol failed to protect motility and fertilization ability. The consequences on DNA methylation were assessed using Reduced Representation Bisulfite Sequencing (RRBS). Sperm cryopreservation did not thoroughly impact DNA methylation, although 335-564 differentially methylated cytosines were characterized depending on the cryoprotectant. Very few of them were shared between cryoprotectants, and no correlation with the extent of cellular damage was found. Our study showed that DNA methylation was only slightly altered after sperm cryopreservation, and this may render further analysis of the risk for the progeny very challenging.
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Affiliation(s)
| | | | - Amin Sayyari
- Department of Production Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Ås, Norway
| | - Audrey Laurent
- INRAE, Fish Physiology and Genomics, UR 1037, Rennes, France.
| | - Catherine Labbé
- INRAE, Fish Physiology and Genomics, UR 1037, Rennes, France.
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5
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Ohki D, Yamamichi N, Sakaguchi Y, Takahashi Y, Kageyama‐Yahara N, Yamamichi M, Takeuchi C, Tsuji Y, Sakai Y, Sakurai K, Tomida S, Koike K, Fujishiro M. Transcriptome of sessile serrated adenoma/polyps is associated with MSI-high colorectal cancer and decreased expression of CDX2. Cancer Med 2022; 11:5066-5078. [PMID: 35535692 PMCID: PMC9761061 DOI: 10.1002/cam4.4810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/21/2022] [Accepted: 04/25/2022] [Indexed: 02/03/2023] Open
Abstract
The objective of this study was to elucidate the molecular background of sessile serrated adenoma/polyp (SSA/P) endoscopically resected with comprehensive gene expression analysis. Gene expression profiling was performed for 10 tumor-normal pairs of SSA/P. Cluster analysis, gene set enrichment analysis (GSEA), and consensus molecular subtype (CMS) classification of colorectal cancer (CRC) were applied to our transcriptome analysis. Unsupervised cluster analysis showed that the gene expression profile of SSA/Ps is different from that of adjacent normal epithelial cells, even in the very early stage of tumorigenesis. According to the CMS classification, our microarray data indicated that SSA/Ps were classified as CMS1. GSEA demonstrated a strong association between SSA/P and microsatellite instability-high (MSI-H) CRC (p < 10-5 ). Transcriptome analysis of five MSI-related genes (MSH2, MSH6, MLH1, PMS1, and PMS2) and five CRC-related genes (BRAF, KRAS, APC, TP53, and CDX2) showed that CDX2 expression was most severely decreased in SSA/P. Immunohistochemical staining confirmed that CDX2 protein was reduced compared with the surrounding mucosa. Direct sequencing of the BRAF gene showed that the BRAF V600E mutation was detected in only nine of 36 cases. In a mouse model, BRAF, APC, or CDX2 deficiency indicated that the gene expression pattern with loss of CDX2 is more similar to our SSA/Ps compared with those induced by BRAF or APC mutation. Transcriptome analysis of SSA/Ps showed characteristic gene expression with a strong resemblance to MSI-H CRC. Downregulation of CDX2 expression is an essential molecular mechanism involved in the initial stage of SSA/P tumorigenesis. (UMIN000027365).
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Affiliation(s)
- Daisuke Ohki
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoTokyoJapan
| | - Nobutake Yamamichi
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoTokyoJapan
| | - Yoshiki Sakaguchi
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoTokyoJapan
| | - Yu Takahashi
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoTokyoJapan
| | - Natsuko Kageyama‐Yahara
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoTokyoJapan
| | - Mitsue Yamamichi
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoTokyoJapan
| | - Chihiro Takeuchi
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoTokyoJapan
| | - Yosuke Tsuji
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoTokyoJapan
| | - Yasuhiro Sakai
- Department of Joint Research Laboratory of Clinical MedicineFujita Health University School of MedicineAichiJapan
| | - Kouhei Sakurai
- Department of Joint Research Laboratory of Clinical MedicineFujita Health University School of MedicineAichiJapan
| | - Shuta Tomida
- Center for Comprehensive Genomic MedicineOkayama University HospitalOkayamaJapan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoTokyoJapan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoTokyoJapan
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6
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Functional diversity in the RAS subfamily of small GTPases. Biochem Soc Trans 2022; 50:921-933. [PMID: 35356965 DOI: 10.1042/bst20211166] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/15/2022] [Accepted: 03/21/2022] [Indexed: 12/12/2022]
Abstract
RAS small GTPases regulate important signalling pathways and are notorious drivers of cancer development and progression. While most research to date has focused on understanding and addressing the oncogenic potential of three RAS oncogenes: HRAS, KRAS, and NRAS; the full RAS subfamily is composed of 35 related GTPases with diverse cellular functions. Most remain deeply understudied despite strong evolutionary conservation. Here, we highlight a group of 17 poorly characterized RAS GTPases that are frequently down-regulated in cancer and evidence suggests may function not as oncogenes, but as tumour suppressors. These GTPases remain largely enigmatic in terms of their cellular function, regulation, and interaction with effector proteins. They cluster within two families we designate as 'distal-RAS' (D-RAS; comprised of DIRAS, RASD, and RASL10) and 'CaaX-Less RAS' (CL-RAS; comprised of RGK, NKIRAS, RERG, and RASL11/12 GTPases). Evidence of a tumour suppressive role for many of these GTPases supports the premise that RAS subfamily proteins may collectively regulate cellular proliferation.
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7
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Mitra S, Paramaguru R, Das P, Katti SV. Preneoplastic Lesions and Polyps of the Gastrointestinal Tract. SURGICAL PATHOLOGY OF THE GASTROINTESTINAL SYSTEM 2022:593-698. [DOI: 10.1007/978-981-16-6395-6_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Ideta T, Li B, Flynn C, Igarashi Y, Lowman G, Looney T, Devers TJ, Birk J, Forouhar F, Giardina C, Rosenberg DW. The Epithelial-Stromal Microenvironment in Early Colonic Neoplasia. Mol Cancer Res 2021; 20:56-61. [PMID: 34670862 DOI: 10.1158/1541-7786.mcr-21-0202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 08/12/2021] [Accepted: 10/15/2021] [Indexed: 12/31/2022]
Abstract
Stromal cells play a central role in promoting the progression of colorectal cancer. Here, we analyze molecular changes within the epithelial and stromal compartments of dysplastic aberrant crypt foci (ACF) formed in the ascending colon, where rapidly developing interval cancers occur. We found strong activation of numerous neutrophil/monocyte chemokines, consistent with localized inflammation. The data also indicated a decrease in interferon signaling and cell-based immunity. The immune checkpoint and T-cell exhaustion gene PDCD1 was one of the most significantly upregulated genes, which was accompanied by a decrease in cytotoxic T-cell effector gene expression. In addition, CDKN2A expression was strongly upregulated in the stroma and downregulated in the epithelium, consistent with diverse changes in senescence-associated signaling on the two tissue compartments. IMPLICATIONS: Decreased CD8 T-cell infiltration within proximal colon ACF occurs within the context of a robust inflammatory response and potential stromal cell senescence, thus providing new insight into potential promotional drivers for tumors in the proximal colon.
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Affiliation(s)
- Takayasu Ideta
- Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut
| | - Boyang Li
- Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut
| | - Christopher Flynn
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Yuichi Igarashi
- Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut
| | | | - Tim Looney
- ThermoFisher Scientific, South San Francisco, California
| | - Thomas J Devers
- Division of Gastroenterology, The University of Connecticut Health Center, Farmington, Connecticut
| | - John Birk
- Division of Gastroenterology, The University of Connecticut Health Center, Farmington, Connecticut
| | - Faripour Forouhar
- Department of Anatomic Pathology, John Dempsey Hospital, The University of Connecticut Health Center, Farmington, Connecticut
| | - Charles Giardina
- Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut
| | - Daniel W Rosenberg
- Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut.
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9
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Takahashi S, Okamoto K, Tanahashi T, Fujimoto S, Nakagawa T, Bando M, Ma B, Kawaguchi T, Fujino Y, Mitsui Y, Kitamura S, Miyamoto H, Sato Y, Muguruma N, Bando Y, Sato T, Fujimori T, Takayama T. S100P Expression via DNA Hypomethylation Promotes Cell Growth in the Sessile Serrated Adenoma/Polyp-Cancer Sequence. Digestion 2021; 102:789-802. [PMID: 33395688 DOI: 10.1159/000512575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 10/26/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS Sessile serrated adenomas/polyps (SSA/Ps) are a putative precursor lesion of colon cancer. Although the relevance of DNA hypermethylation in the SSA/P-cancer sequence is well documented, the role of DNA hypomethylation is unknown. We investigated the biological relevance of DNA hypomethylation in the SSA/P-cancer sequence by using 3-dimensional organoids of SSA/P. METHODS We first analyzed hypomethylated genes using datasets from our previous DNA methylation array analysis on 7 SSA/P and 2 cancer in SSA/P specimens. Expression levels of hypomethylated genes in SSA/P specimens were determined by RT-PCR and immunohistochemistry. We established 3-dimensional SSA/P organoids and performed knockdown experiments using a lentiviral shRNA vector. DNA hypomethylation at CpG sites of the gene was quantitated by MassARRAY analysis. RESULTS The mean number of hypomethylated genes in SSA/P and cancer in SSA/P was 41.6 ± 27.5 and 214 ± 19.8, respectively, showing a stepwise increment in hypomethylation during the SSA/P-cancer sequence. S100P, S100α2, PKP3, and MUC2 were most commonly hypomethylated in SSA/P specimens. The mRNA and protein expression levels of S100P, S100α2, and MUC2 were significantly elevated in SSA/P compared with normal colon tissues, as revealed by RT-PCR and immunohistochemistry, respectively. Among these, mRNA and protein levels were highest for S100P. Knockdown of the S100P gene using a lentiviral shRNA vector in 3-dimensional SSA/P organoids inhibited cell growth by >50% (p < 0.01). The mean diameter of SSA/P organoids with S100P gene knockdown was significantly smaller compared with control organoids. MassARRAY analysis of DNA hypomethylation in the S100P gene revealed significant hypomethylation at specific CpG sites in intron 1, exon 1, and the 5'-flanking promoter region. CONCLUSION These results suggest that DNA hypomethylation, including S100P hypomethylation, is supposedly associated with the SSA/P-cancer sequence. S100P overexpression via DNA hypomethylation plays an important role in promoting cell growth in the SSA/P-cancer sequence.
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Affiliation(s)
- Sayo Takahashi
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Toshihito Tanahashi
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Shota Fujimoto
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Tadahiko Nakagawa
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Masahiro Bando
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Beibei Ma
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Tomoyuki Kawaguchi
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Yasuteru Fujino
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Yasuhiro Mitsui
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Shinji Kitamura
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Yasushi Sato
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Naoki Muguruma
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Yoshimi Bando
- Division of Pathology, Tokushima University Hospital, Tokushima, Japan
| | - Toshiro Sato
- Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan
| | | | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan,
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10
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MacKenzie DJ, Robertson NA, Rather I, Reid C, Sendzikaite G, Cruickshanks H, McBryan T, Hodges A, Pritchard C, Blyth K, Adams PD. DNMT3B Oncogenic Activity in Human Intestinal Cancer Is Not Linked to CIMP or BRAFV600E Mutation. iScience 2020; 23:100838. [PMID: 32058953 PMCID: PMC7000804 DOI: 10.1016/j.isci.2020.100838] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 08/22/2019] [Accepted: 01/09/2020] [Indexed: 12/24/2022] Open
Abstract
Approximately 10% of human colorectal cancer (CRC) are associated with activated BRAFV600E mutation, typically in absence of APC mutation and often associated with a CpG island methylator (CIMP) phenotype. To protect from cancer, normal intestinal epithelial cells respond to oncogenic BRAFV600E by activation of intrinsic p53 and p16-dependent tumor suppressor mechanisms, such as cellular senescence. Conversely, CIMP is thought to contribute to bypass of these tumor suppressor mechanisms, e.g. via epigenetic silencing of tumor suppressor genes, such as p16. It has been repeatedly proposed that DNMT3B is responsible for BRAFV600E-induced CIMP in human CRC. Here we set out to test this by in silico, in vitro, and in vivo approaches. We conclude that although both BRAFV600E and DNMT3B harbor oncogenic potential in vitro and in vivo and show some evidence of cooperation in tumor promotion, they do not frequently cooperate to promote CIMP and human intestinal cancer.
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Affiliation(s)
| | - Neil A Robertson
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Iqbal Rather
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Claire Reid
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | | | | | - Tony McBryan
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Andrew Hodges
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Catrin Pritchard
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Karen Blyth
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; Cancer Research UK Beatson Institute, Glasgow, UK
| | - Peter D Adams
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
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11
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Liu C, Fennell LJ, Bettington ML, Walker NI, Dwine J, Leggett BA, Whitehall VLJ. DNA methylation changes that precede onset of dysplasia in advanced sessile serrated adenomas. Clin Epigenetics 2019; 11:90. [PMID: 31200767 PMCID: PMC6570920 DOI: 10.1186/s13148-019-0691-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 06/04/2019] [Indexed: 12/31/2022] Open
Abstract
Background Sessile serrated adenomas (SSAs) are common polyps which give rise to 20–30% of colorectal cancer (CRC). SSAs display clinicopathologic features which present challenges in surveillance, including overrepresentation in young patients, proclivity for the proximal colon and rarity of histologic dysplasia (referred to then as SSAs with dysplasia, SSADs). Once dysplasia develops, there is rapid progression to CRC, even at a small size. There is therefore a clinical need to separate the “advanced” SSAs at high risk of progression to SSAD and cancer from ordinary SSAs. Since SSAs are known to accumulate methylation over time prior to the development of dysplasia, SSAD backgrounds (the remnant SSA present within an SSAD) likely harbour additional methylation events compared with ordinary SSAs. We therefore performed MethyLight and comprehensive methylation array (Illumina MethylationEPIC) on 40 SSAD backgrounds and 40 matched ordinary SSAs, and compared the methylation results with CRC methylation, CRC expression and immunohistochemical data. Results SSAD backgrounds demonstrated significant hypermethylation of CpG islands compared with ordinary SSAs, and the proportion of hypermethylated probes decreased progressively in the shore, shelf and open sea regions. Hypomethylation occurred in concert with hypermethylation, which showed a reverse pattern, increasing progressively away from the island regions. These methylation changes were also identified in BRAF-mutant hypermethylated CRCs. When compared with CRC expression data, SV2B, MLH1/EPM2AIP1, C16orf62, RCOR3, BAIAP3, OGDHL, HDHD3 and ATP1B2 demonstrated both promoter hypermethylation and decreased expression. Although SSAD backgrounds were histologically indistinguishable from ordinary SSAs, MLH1 methylation was detectable via MethyLight in 62.9% of SSAD backgrounds, and focal immunohistochemical MLH1 loss was seen in 52.5% of SSAD backgrounds. Conclusions Significant hyper- and hypomethylation events occur during SSA progression well before the development of histologically identifiable changes. Methylation is a heterogeneous process within individual SSAs, as typified by MLH1, where both MLH1 methylation and focal immunohistochemical MLH1 loss can be seen in the absence of dysplasia. This heterogeneity is likely a generalised phenomenon and should be taken into account in future methylation-based studies and the development of clinical methylation panels. Electronic supplementary material The online version of this article (10.1186/s13148-019-0691-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Cheng Liu
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia. .,Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia. .,Envoi Specialist Pathologists, Brisbane, QLD, Australia.
| | - Lochlan J Fennell
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.,Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Mark L Bettington
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,Envoi Specialist Pathologists, Brisbane, QLD, Australia
| | - Neal I Walker
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,Envoi Specialist Pathologists, Brisbane, QLD, Australia
| | - Joel Dwine
- Envoi Specialist Pathologists, Brisbane, QLD, Australia
| | - Barbara A Leggett
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.,Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
| | - Vicki L J Whitehall
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.,Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,Department of Chemical Pathology, Pathology Queensland, Brisbane, QLD, Australia
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12
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Quintanilla I, López-Cerón M, Jimeno M, Cuatrecasas M, Zabalza M, Moreira L, Alonso V, Rodríguez de Miguel C, Muñoz J, Castellvi-Bel S, Llach J, Castells A, Balaguer F, Camps J, Pellisé M. Rectal Aberrant Crypt Foci in Humans Are Not Surrogate Markers for Colorectal Cancer Risk. Clin Transl Gastroenterol 2019; 10:e00047. [PMID: 31136360 PMCID: PMC6613864 DOI: 10.14309/ctg.0000000000000047] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 02/22/2019] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Over the past 20 years, aberrant crypt foci (ACF) have emerged as potential precursors and biomarkers for colorectal cancer (CRC). However, data regarding their molecular pathogenesis, as well as their endoscopic and histological identification, remain inconsistent. METHODS A wide cohort of ACF from 100 control subjects and 100 case patients, including patients with adenoma and CRC, were characterized for endoscopic, morphologic, and molecular features. RESULTS We observed that among all the endoscopic features evaluated, only the number of large ACF correlated with CRC risk (P = 0.003), whereas the histological classification, as assessed by 2 different pathologists, was inconsistent and did not differ between control and case patients. Moreover, only a few APC and BRAF mutations and no microsatellite instability were detected in our samples. KRAS mutations were detected in 16.3% of ACF samples, which also exhibited increased MGMT hypermethylation. However, none of those events were found to be predictive of CRC risk. DISCUSSION Although ACF might be preneoplastic lesions of the colon, they are not suitable biomarkers for assessing CRC progression.
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Affiliation(s)
- Isabel Quintanilla
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - María López-Cerón
- Gastroenterology Department, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
| | - Mireya Jimeno
- Pathology Department, Centre de Diagnòstic Biomèdic, Hospital Clínic and Banc de Tumors-Biobanc Clinic-IDIBAPS-XBTC, Barcelona, Catalonia, Spain
| | - Miriam Cuatrecasas
- Pathology Department, Centre de Diagnòstic Biomèdic, Hospital Clínic and Banc de Tumors-Biobanc Clinic-IDIBAPS-XBTC, Barcelona, Catalonia, Spain
| | - Michel Zabalza
- Gastroenterology Department, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
| | - Leticia Moreira
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Virginia Alonso
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Cristina Rodríguez de Miguel
- Gastroenterology Department, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
| | - Jennifer Muñoz
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Sergi Castellvi-Bel
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Josep Llach
- Gastroenterology Department, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
| | - Antoni Castells
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), University of Barcelona, Barcelona, Spain
- Gastroenterology Department, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
| | - Francesc Balaguer
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), University of Barcelona, Barcelona, Spain
- Gastroenterology Department, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
| | - Jordi Camps
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Maria Pellisé
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), University of Barcelona, Barcelona, Spain
- Gastroenterology Department, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
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13
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Miyamoto Y, Muguruma N, Fujimoto S, Okada Y, Kida Y, Nakamura F, Tanaka K, Nakagawa T, Kitamura S, Okamoto K, Miyamoto H, Sato Y, Takayama T. Epidermal growth factor receptor-targeted molecular imaging of colorectal tumors: Detection and treatment evaluation of tumors in animal models. Cancer Sci 2019; 110:1921-1930. [PMID: 30973663 PMCID: PMC6549923 DOI: 10.1111/cas.14020] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 04/03/2019] [Accepted: 04/08/2019] [Indexed: 12/13/2022] Open
Abstract
To overcome the problem of overlooking colorectal tumors, a new and highly sensitive modality of colonoscopy is needed. Moreover, it is also important to establish a new modality to evaluate viable tumor volume in primary lesions of colorectal cancer (CRC) during chemotherapy. Therefore, we carried out molecular imaging of colorectal tumors targeting epidermal growth factor receptor (EGFR), which is highly expressed on tumor cells, for evaluating chemotherapeutic efficacy and for endoscopic detection of colorectal adenomas. We first attempted to image five CRC cell lines with various levels of EGFR expression using an Alexa Fluor-labeled anti-EGFR monoclonal antibody (AF-EGFR-Ab). A strong fluorescence signal was observed in the cells depending on the level of EGFR expression. When nude mice xenografted with LIM1215 CRC cells, which highly express EGFR, were i.v. injected with AF-EGFR-Ab, a strong fluorescence signal appeared in the tumor with a high signal to noise ratio, peaking at 48 hours after injection and then gradually decreasing, as shown using an IVIS Spectrum system. When the xenografted mice were treated with 5-fluorouracil, fluorescence intensity in the tumor decreased in proportion to the viable tumor cell volume. Moreover, when the colorectum of azoxymethane-treated rats was observed using a thin fluorescent endoscope with AF-EGFR-Ab, all 10 small colorectal adenomas (≤3 mm) were detected with a clear fluorescence signal. These preliminary results of animal experiments suggest that EGFR-targeted fluorescent molecular imaging may be useful for quantitatively evaluating cell viability in CRC during chemotherapy, and also for detecting small adenomas using a fluorescent endoscope.
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Affiliation(s)
- Yoshihiko Miyamoto
- Department of Gastroenterology and OncologyUniversity of Tokushima Faculty of Medicine Graduate School of Medical SciencesTokushimaJapan
| | - Naoki Muguruma
- Department of Gastroenterology and OncologyUniversity of Tokushima Faculty of Medicine Graduate School of Medical SciencesTokushimaJapan
| | - Shota Fujimoto
- Department of Gastroenterology and OncologyUniversity of Tokushima Faculty of Medicine Graduate School of Medical SciencesTokushimaJapan
| | - Yasuyuki Okada
- Department of Gastroenterology and OncologyUniversity of Tokushima Faculty of Medicine Graduate School of Medical SciencesTokushimaJapan
| | - Yoshifumi Kida
- Department of Gastroenterology and OncologyUniversity of Tokushima Faculty of Medicine Graduate School of Medical SciencesTokushimaJapan
| | - Fumika Nakamura
- Department of Gastroenterology and OncologyUniversity of Tokushima Faculty of Medicine Graduate School of Medical SciencesTokushimaJapan
| | - Kumiko Tanaka
- Department of Gastroenterology and OncologyUniversity of Tokushima Faculty of Medicine Graduate School of Medical SciencesTokushimaJapan
| | - Tadahiko Nakagawa
- Department of Health and NutritionUniversity of Shimane Faculty of NursingIzumoJapan
| | - Shinji Kitamura
- Department of Gastroenterology and OncologyUniversity of Tokushima Faculty of Medicine Graduate School of Medical SciencesTokushimaJapan
| | - Koichi Okamoto
- Department of Gastroenterology and OncologyUniversity of Tokushima Faculty of Medicine Graduate School of Medical SciencesTokushimaJapan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and OncologyUniversity of Tokushima Faculty of Medicine Graduate School of Medical SciencesTokushimaJapan
| | - Yasushi Sato
- Department of Community Medicine for Gastroenterology and OncologyTokushima University Graduate SchoolTokushimaJapan
| | - Tetsuji Takayama
- Department of Gastroenterology and OncologyUniversity of Tokushima Faculty of Medicine Graduate School of Medical SciencesTokushimaJapan
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14
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Cappellesso R, Lo Mele M, Munari G, Rosa-Rizzotto E, Guido E, De Lazzari F, Pilati P, Tonello M, Farinati F, Realdon S, Fassan M, Rugge M. Molecular characterization of "sessile serrated" adenoma to carcinoma transition in six early colorectal cancers. Pathol Res Pract 2019; 215:957-962. [PMID: 30738693 DOI: 10.1016/j.prp.2019.02.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 01/21/2019] [Accepted: 02/01/2019] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is a heterogeneous group of diseases both from the morphological and molecular point of view. The sessile serrated adenoma/polyp (SSA/P) has been proposed as the precursor lesion of CRCs characterized by CpG island methylator phenotype (CIMP), DNA mismatch repair (MMR) system deficiency, and BRAF gene mutations. However, no study so far investigated the molecular landscape of "sessile serrated" adenoma to carcinoma transition in early CRCs. Six formalin-fixed paraffin-embedded CRCs developed within SSA/P were profiled for the immunohistochemical expression of MMR proteins (MLH1, MSH2, MSH6, PMS2, and Ep-CAM), p16, and β-catenin. DNA was extracted from the two components of each sample, after microdissection, and characterized for CIMP status and by applying a custom hotspot multigene mutational profiling of 164 hotspot regions of eleven CRC-associated genes (AKT1, APC, BRAF, CTNNB1, KIT, KRAS, NRAS, PDGFRA, PIK3CA, PTEN, and TP53). Five out of the six CRCs shared the same molecular profile (i.e. CIMP positive, MSI status, and BRAF mutation) with their SSA/P components. One out of five CRCs was also APC mutated, whereas another one showed an additional TP53 mutation. The remaining case was CIMP negative and MMR proficient in both the components, harbored a BRAF mutation in the SSA/P counterpart, whereas the CRC one was APC and TP53 mutated and showed p16 and β-catenin dysregulation. This study provides the molecular evidence that SSA/P, even without cytological dysplasia, is a precursor lesion of CRC and that conventional CRC might arise from mixed polyp.
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Affiliation(s)
- Rocco Cappellesso
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, 35121, Italy
| | - Marcello Lo Mele
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, 35121, Italy
| | - Giada Munari
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, 35121, Italy; Veneto Institute of Oncology - I.R.C.S.S, Padua, 35128, Italy
| | | | - Ennio Guido
- Gastroenterology Unit, S. Antonio Hospital, Padua, 35128, Italy
| | | | - Pierluigi Pilati
- Unit of Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology - I.R.C.S.S, Padua, 35128, Italy
| | - Marco Tonello
- Unit of Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology - I.R.C.S.S, Padua, 35128, Italy; Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, 35128, Italy
| | - Fabio Farinati
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, 35128, Italy
| | - Stefano Realdon
- Unit of Digestive Endoscopy, Veneto Institute of Oncology - I.R.C.S.S, Padua, 35128, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, 35121, Italy.
| | - Massimo Rugge
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, 35121, Italy
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15
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Zheng C, Lin X, Xu X, Wang C, Zhou J, Gao B, Fan J, Lu W, Hu Y, Jie Q, Luo Z, Yang L. Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias. EBioMedicine 2019; 40:695-709. [PMID: 30685387 PMCID: PMC6413327 DOI: 10.1016/j.ebiom.2019.01.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 01/03/2019] [Accepted: 01/07/2019] [Indexed: 12/21/2022] Open
Abstract
Background Mutations in the SLC26A2 gene cause a spectrum of currently incurable human chondrodysplasias. However, genotype-phenotype relationships of SLC26A2-deficient chondrodysplasias are still perplexing and thus stunt therapeutic development. Methods To investigate the causative role of SLC26A2 deficiency in chondrodysplasias and confirm its skeleton-specific pathology, we generated and analyzed slc26a2−/− and Col2a1-Cre; slc26a2fl/fl mice. The therapeutic effect of NVP-BGJ398, an FGFR inhibitor, was tested with both explant cultures and timed pregnant females. Findings Two lethal forms of human SLC26A2-related chondrodysplasias, achondrogenesis type IB (ACG1B) and atelosteogenesis type II (AO2), are phenocopied by slc26a2−/− mice. Unexpectedly, slc26a2−/− chondrocytes are defective for collagen secretion, exhibiting intracellular retention and compromised extracellular deposition of ColII and ColIX. As a consequence, the ATF6 arm of the unfolded protein response (UPR) is preferentially triggered to overactivate FGFR3 signaling by inducing excessive FGFR3 in slc26a2−/− chondrocytes. Consistently, suppressing FGFR3 signaling by blocking either FGFR3 or phosphorylation of the downstream effector favors the recovery of slc26a2−/− cartilage cultures from impaired growth and unbalanced cell proliferation and apoptosis. Moreover, administration of an FGFR inhibitor to pregnant females shows therapeutic effects on pathological features in slc26a2−/− newborns. Finally, we confirm the skeleton-specific lethality and pathology of global SLC26A2 deletion through analyzing the Col2a1-Cre; slc26a2fl/fl mouse line. Interpretation Our study unveils a previously unrecognized pathogenic mechanism underlying ACG1B and AO2, and supports suppression of FGFR3 signaling as a promising therapeutic approach for SLC26A2-related chondrodysplasias. Fund This work was supported by National Natural Science Foundation of China (81871743, 81730065 and 81772377).
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Affiliation(s)
- Chao Zheng
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Xisheng Lin
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Xiaolong Xu
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Cheng Wang
- School of Biomedical Sciences, University of Hong Kong, Hong Kong, China
| | - Jinru Zhou
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Bo Gao
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jing Fan
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Weiguang Lu
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yaqian Hu
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Qiang Jie
- Department of Orthopedic Surgery, HongHui Hospital, Xi'an Jiaotong University, College of Medicine, Xi'an, China
| | - Zhuojing Luo
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China; Medical Research Institute, Northwestern Polytechnical University, Xi'an, China
| | - Liu Yang
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China; Medical Research Institute, Northwestern Polytechnical University, Xi'an, China.
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16
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Mo A, Wu R, Grady JP, Hanley MP, Toro M, Swede H, Devers TJ, Hartman TJ, Rosenberg DW. Associations of dietary fat with risk of early neoplasia in the proximal colon in a population-based case-control study. Cancer Causes Control 2018; 29:667-674. [PMID: 29846845 DOI: 10.1007/s10552-018-1039-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 05/12/2018] [Indexed: 12/12/2022]
Abstract
PURPOSE Excess dietary fat consumption is strongly associated with the risk of colorectal cancer, but less is known about its role in the earliest stages of carcinogenesis, particularly within the proximal colon. In the following case-control study, we evaluated the relationship between the intake of dietary fats and the frequency of early proximal neoplasia [aberrant crypt foci (ACF) or polyps], detectable by high-definition colonoscopy with contrast dye-spray. METHODS Average-risk screening individuals underwent a high-definition colonoscopy procedure as part of larger ongoing clinical study of precancerous lesions in the proximal colon. Dietary fat intake was assessed using the Block Brief Food Frequency Questionnaire, which estimates average dietary intake based on 70 food items. The diets of individuals with no endoscopically identifiable lesions (n = 36) were compared to those with either ACF or polyps detected in the proximal colon. RESULTS In multivariate analysis, high dietary intake of total polyunsaturated fatty acids (PUFAs) and intake of omega-6 and omega-3 fatty acids were positively associated with neoplastic lesions in the proximal colon. When comparing ACF and polyp groups separately, a positive association was observed for both proximal polyps (OR 2.28; CI 1.16-7.09) and ACF (OR 2.86; CI 1.16-7.09) for total PUFA intake. Furthermore, the prevalence of proximal ACF was increased with higher intake of omega-6 (OR 3.54; CI 1.32-9.47) and omega-3 fatty acids (OR 2.29; CI 1.02-5.13), although there was no discernible difference in the omega-6/omega-3 ratio. CONCLUSIONS These results suggest that dietary PUFAs may be positively associated with risk of early neoplasia in the proximal colon. This study provides further evidence that dietary PUFA composition may play an important role in altering the microenvironment within the human colon.
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Affiliation(s)
- Allen Mo
- Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT, 06030-3101, USA.,Colon Cancer Prevention Program, Neag Comprehensive Cancer Center, UConn Health, Farmington, CT, USA
| | - Rong Wu
- Connecticut Institute for Clinical and Translational Science, UConn Health, Farmington, CT, USA
| | - James P Grady
- Connecticut Institute for Clinical and Translational Science, UConn Health, Farmington, CT, USA
| | - Matthew P Hanley
- Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT, 06030-3101, USA.,Colon Cancer Prevention Program, Neag Comprehensive Cancer Center, UConn Health, Farmington, CT, USA
| | - Margaret Toro
- Clinal Trials Office, UConn Health, Farmington, CT, USA
| | - Helen Swede
- Community Medicine and Health Care, UConn Health, Farmington, CT, USA
| | - Thomas J Devers
- Division of Gastroenterology, School of Medicine, UConn Health, Farmington, CT, USA
| | - Terryl J Hartman
- Rollins School of Public Health, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Daniel W Rosenberg
- Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT, 06030-3101, USA. .,Colon Cancer Prevention Program, Neag Comprehensive Cancer Center, UConn Health, Farmington, CT, USA.
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17
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Fujimoto S, Muguruma N, Okamoto K, Kurihara T, Sato Y, Miyamoto Y, Kitamura S, Miyamoto H, Taguchi T, Tsuneyama K, Takayama T. A Novel Theranostic Combination of Near-infrared Fluorescence Imaging and Laser Irradiation Targeting c-KIT for Gastrointestinal Stromal Tumors. Theranostics 2018; 8:2313-2328. [PMID: 29721082 PMCID: PMC5928892 DOI: 10.7150/thno.22027] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 02/27/2018] [Indexed: 01/13/2023] Open
Abstract
It is difficult to distinguish gastrointestinal stromal tumors (GISTs) from other types of submucosal tumors under conventional gastrointestinal endoscopy. We aimed to detect GISTs by molecular fluorescence imaging using a near-infrared (NIR) photosensitizer (IR700)-conjugated anti-c-KIT antibody and to treat GISTs by photoimmunotherapy with NIR irradiation as a non-invasive theranostic procedure. We also investigated the therapeutic mechanisms. Methods: Human GIST cell lines GIST-T1 and GIST-882M were incubated with IR700-conjugated anti-c-KIT antibody, IR700-12A8, and observed by confocal laser microscopy. Mice with GIST-T1 xenografts or rats with orthotopic xenografts were injected with IR700-12A8 or AF488-conjugated antibody, and observed under IVIS or autofluorescence imaging (AFI) endoscopy. GIST cells were treated with IR700-12A8 and NIR light in vitro and vivo, and cell viability, histology and apoptosis were evaluated. Results: Strong red fluorescence of IR700-12A8 was observed on the cell membrane of GIST cells and was gradually internalized into the cytoplasm. Tumor-specific accumulation of IR700-12A8 was observed in GIST-T1 xenografts in mice. Under AFI endoscopy, a strong fluorescence signal was observed in orthotopic GIST xenografts in rats through the normal mucosa covering the tumor. The percentage of dead cells significantly increased in a light-dose-dependent manner and both acute necrotic and late apoptotic cell death was observed with annexin/PI staining. Cleaved PARP expression was significantly increased after IR700-12A8-mediated NIR irradiation, which was almost completely reversed by NaN3. All xenograft tumors (7/7) immediately regressed and 4/7 tumors completely disappeared after IR700-12A8-mediated NIR irradiation. Histologic assessment and TUNEL staining revealed apoptosis in the tumors. Conclusion: NIR fluorescence imaging using IR700-12A8 and subsequent NIR irradiation could be a very effective theranostic technology for GIST, the underlying mechanism of which appears to involve acute necrosis and supposedly late apoptosis induced by singlet oxygen.
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Affiliation(s)
- Shota Fujimoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Naoki Muguruma
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Takeshi Kurihara
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Yasushi Sato
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Yoshihiko Miyamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Shinji Kitamura
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Takahiro Taguchi
- Division of Human Health & Medical Science, Graduate School of Kuroshio Science, Kochi University, Nankoku, Kochi, Japan
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
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Ghosh S, Gupta B, Verma P, Vishnubathla S, Pal S, Dash NR, Gupta SD, Das P. Topographic, histological and molecular study of aberrant crypt foci identified in human colon in different clinical groups. Intest Res 2018; 16:116-125. [PMID: 29422806 PMCID: PMC5797258 DOI: 10.5217/ir.2018.16.1.116] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Revised: 09/23/2017] [Accepted: 09/27/2017] [Indexed: 12/12/2022] Open
Abstract
Background/Aims Aberrant crypt foci (ACF) are early microscopic lesions of the colonic mucosa, which can be detected by magnified chromoendoscopy. Herein, we have investigated whether ACF identified in different clinical groups can be differentiated based on their characteristics. Methods Macroscopically unremarkable mucosal flaps were collected from 270 fresh colectomies and divided into 3 clinical groups: colorectal carcinoma (group A), disease controls having known pre-neoplastic potential (group Bc), and disease controls without risk of carcinoma development (group Bn). Topographic and histologic analysis, immunohistochemistry, and molecular studies (high-resolution melt curve analysis, real-time polymerase chain reaction, and Sanger sequencing) were conducted for certain neoplasia-associated markers. Results ACF were seen in 107 cases, out of which 72 were left colonic ACF and 35 right colonic ACF (67.2% vs. 32.7%, P=0.02). The overall density of left colonic ACF was 0.97/cm, which was greater than the right colonic ACF density of 0.81/cm. Hypercrinia was present in 41 out of 72 left colonic ACF and in 14 out of 35 right colonic ACF (P=0.01). Immunohistochemical expression of p53 was also greater in left colonic ACF than in right colonic ACF (60.5% vs. 38.2%, P=0.03). However, ACF identified among the 3 clinical groups did not show any distinguishing topographic, histological, or genetic changes. Conclusions Left colonic ACF appear to be high-risk based on their morphological and prototypic tumor marker signature. ACF identified in different clinical groups do not show significant genotypic or topographic differences. Further detailed genetic studies are required to elucidate them further.
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Affiliation(s)
- Shouriyo Ghosh
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Brijnandan Gupta
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Pavan Verma
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | | | - Sujoy Pal
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Nihar R Dash
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | | | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
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Abstract
Tumor-associated gangliosides play important roles in regulation of signal transduction induced by growth-factor receptors including EGFR, FGFR, HGF and PDGFR in a specific microdomain called glycosynapse in the cancer cell membranes, and in interaction with glycan recognition molecules involved in cell adhesion and immune regulation including selectins and siglecs. As the genes involved in the synthesis and degradation of tumor-associated gangliosides were identified, biological functions became clearer from the experimental results employing forced overexpression and/or knockdown/knockout of the genes. Studies on the regulatory mechanisms for their expression also achieved great advancements. Epigenetic silencing of glycan-related genes is a dominant mechanism in glycan alteration at early stages of carcinogenesis. Development of hypoxia resistance involving activation of a transcription factor HIF, and acquisition of cancer stem cell-like characteristics through epithelial-mesenchymal transition are important mechanisms for glycan modulations in the later stages of cancer progression. In the initial stages of studies, the gangliosides which specifically appear in cancers attracted attention under the name of tumor-associated gangliosides. However, it became apparent that not only the cancer-associated gangliosides but also the normal gangliosides present in nonmalignant cells and tissues perform important biological functions, and some of them tend to disappear in cancer cells resulting in the loss of the physiological functions, and this sometimes facilitates progression of cancers.
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20
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Drew DA, Mo A, Grady JJ, Stevens RG, Levine JB, Brenner BM, Anderson JC, Forouhar F, O'Brien MJ, Devers TJ, Rosenberg DW. Proximal Aberrant Crypt Foci Associate with Synchronous Neoplasia and Are Primed for Neoplastic Progression. Mol Cancer Res 2017; 16:486-495. [PMID: 29222172 DOI: 10.1158/1541-7786.mcr-17-0380] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 10/11/2017] [Accepted: 11/08/2017] [Indexed: 12/27/2022]
Abstract
Aberrant crypt foci (ACF) are the earliest morphologically identifiable lesion found within the human colon. Despite their relatively high frequency in the distal colon, few studies have examined the molecular characteristics of ACF within the proximal colon. In the following study, clinical participants (n = 184) were screened for ACF using high-definition chromoendoscopy with contrast dye-spray. Following pathologic confirmation, ACF biopsies were subjected to laser capture microdissection (LCM), and epithelial cells were evaluated for somatic mutations with a customized colorectal cancer mutation panel using DNA-mass spectrometry. Samples were further characterized for microsatellite instability (MSI). Logistic models were used to associate proximal ACF with synchronous (detected during the same procedure) neoplasia. Thirty-nine percent of participants had at least one histologically confirmed proximal ACF. Individuals with a proximal ACF were significantly more likely to present with a synchronous neoplasm (P = 0.001), and specifically, a proximal, tubular, or tubulovillous adenoma (multivariable OR = 2.69; 95% confidence interval, 1.12-6.47; P = 0.027). Proximal ACF were more likely to be dysplastic (52%) compared with distal ACF (13%; P < 0.0001). Somatic mutations to APC, BRAF, KRAS, NRAS, and ERBB2 were detected in 37% of proximal ACF. Hyperplastic ACF were more often MSI-high, but there were no differences in MSI status observed by colonic location. In summary, ACF are identified in the proximal colons of approximately 40% of individuals undergoing chromoendoscopy and more often in patients with synchronous proximal adenomas.Implications: This study provides the most complete set of data, to date, that ACF represent the earliest step in the adenoma-carcinoma sequence but remain below the detection limit of conventional endoscopy.Visual Overview: http//mcr.accrjournals.org/content/molcanres/16/3/486/F1.large.jpg Mol Cancer Res; 16(3); 486-95. ©2017 AACR.
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Affiliation(s)
- David A Drew
- Center for Molecular Medicine, University of Connecticut Health, Farmington, Connecticut
| | - Allen Mo
- Center for Molecular Medicine, University of Connecticut Health, Farmington, Connecticut
| | - James J Grady
- Connecticut Institute for Clinical and Translational Science, University of Connecticut Health, Farmington, Connecticut
| | - Richard G Stevens
- Division of Epidemiology and Biostatistics, University of Connecticut Health, Farmington, Connecticut.,Department of Community Medicine and Health Care
| | - Joel B Levine
- Colon Cancer Prevention Program, University of Connecticut Health, Farmington, Connecticut
| | - Bruce M Brenner
- Division of Gastroenterology, University of Connecticut Health, Farmington, Connecticut
| | - Joseph C Anderson
- Division of Gastroenterology, University of Connecticut Health, Farmington, Connecticut
| | - Faripour Forouhar
- Department of Anatomic Pathology, School of Medicine, University of Connecticut Health, Farmington, Connecticut
| | - Michael J O'Brien
- Department of Pathology, School of Medicine, Boston University, Boston, Massachusetts
| | - Thomas J Devers
- Division of Gastroenterology, University of Connecticut Health, Farmington, Connecticut
| | - Daniel W Rosenberg
- Center for Molecular Medicine, University of Connecticut Health, Farmington, Connecticut. .,Colon Cancer Prevention Program, University of Connecticut Health, Farmington, Connecticut
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Hashimoto T, Yamashita S, Yoshida H, Taniguchi H, Ushijima T, Yamada T, Saito Y, Ochiai A, Sekine S, Hiraoka N. WNT Pathway Gene Mutations Are Associated With the Presence of Dysplasia in Colorectal Sessile Serrated Adenoma/Polyps. Am J Surg Pathol 2017; 41:1188-1197. [PMID: 28614199 DOI: 10.1097/pas.0000000000000877] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Sessile serrated adenoma/polyps (SSA/Ps) are believed to be the major precursor of serrated pathway-derived colorectal carcinomas. To better characterize the process of progression from SSA/Ps to carcinomas, we analyzed 46 SSA/Ps with dysplasia and 45 SSA/Ps without dysplasia using targeted next-generation sequencing and immunohistochemistry. Among the WNT pathway genes analyzed, protein-truncating mutations of RNF43, APC, and ZNRF3 were identified in 23 (50%), 4 (9%), and 3 (7%) SSA/Ps with dysplasia, respectively. In contrast, SSA/Ps without dysplasia rarely had WNT pathway gene mutations, except for 3 lesions with RNF43 mutations (7%). None of the SSA/Ps had CTNNB1 mutations or RSPO fusions. Thus, WNT pathway gene mutations were more common in SSA/Ps with dysplasia than in SSA/Ps without dysplasia (P=3.0×10). Consistently, nuclear β-catenin accumulation and MYC overexpression, indicative of active WNT signaling, were present in most of the SSA/Ps with dysplasia, but were rare in those without dysplasia. BRAF (86%) or KRAS mutations (7%) were identified in the majority of SSA/Ps, regardless of the presence or absence of dysplasia. MLH1 expression was lost in 14 SSA/Ps with dysplasia (30%). The majority of MLH1-deficient SSA/Ps with dysplasia had RNF43 mutations (86%), most of which were frameshift mutations involving mononucleotide repeats. In contrast, MLH1-retained lesions had less frequent RNF43 mutations with no hot spots (34%), and 4 had APC mutations (13%). These results suggest that WNT pathway gene mutations are involved in the development of dysplasia in SSA/Ps and that MLH1-deficient and MLH1-retained SSA/Ps with dysplasia exhibit distinct mutation profiles of WNT pathway genes.
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Affiliation(s)
- Taiki Hashimoto
- *Division of Pathology and Clinical Laboratories ∥Endoscopy Division, National Cancer Center Hospital †Course of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine ‡Division of Epigenomics §Division of Chemotherapy and Clinical Research #Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo ¶Division of Pathology, Research Center for Innovative Oncology, National Cancer Center, Chiba, Japan
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Tamoto A, Yashima K, Hosoda K, Yamamoto S, Kawata S, Ikebuchi Y, Matsumoto K, Kawaguchi K, Harada K, Murawaki Y, Isomoto H. Protein expression of Fragile Histidine Triad and cyclooxgenase-2 in serrated neoplasia of the colorectum. Oncol Lett 2017; 14:3683-3688. [PMID: 28927131 PMCID: PMC5587971 DOI: 10.3892/ol.2017.6634] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 03/09/2017] [Indexed: 12/20/2022] Open
Abstract
The adenoma-carcinoma sequence (ACS) and the serrated pathway are two distinct developmental routes leading to the formation of colorectal carcinoma (CRC). However, the mechanism triggered by the serrated pathway remains unclear. Therefore, to clarify the molecular and clinicopathological characteristics of the serrated tumorigenic pathway, immunohistochemistry was used to examine the expression of Fragile Histidine Triad (FHIT), cyclooxygenase-2 (COX-2), MutL homolog 1 (MLH1), MutS protein homolog 2 (MSH2) and P53 in endoscopically resected samples of 62 serrated polyps. These samples included 20 hyperplastic polyps (HPs), 16 traditional serrated adenomas (TSAs), 26 sessile serrated adenoma/polyps (SSA/Ps), 20 non-serrated adenomas, 20 carcinoma in adenomas (CIAs) and 18 early pure CRCs without any adenoma component (EPCs). FHIT expression was markedly reduced or absent in 50% of TSA samples, 92.3% of SSA/Ps and 44% of EPCs, but only rarely in HPs, non-serrated adenomas and CIAs. COX-2 expression was more common in non-serrated adenomas compared with in serrated polyps, and was present in 25 and 3.2% of the cases respectively (P<0.01). Furthermore, COX-2 expression was more frequent in CIAs (60%) compared with in EPCs (22.2%; P<0.05). The incidence of negative COX-2 expression was higher in FHIT-negative SSA/Ps compared with in FHIT-positive SSA/Ps (P=0.08). A total of 16.7% of EPC samples and 11.5% of SSA/Ps demonstrated a loss of MLH1/MSH2 expression, but none of the other tumor types did. P53 overexpression was significantly increased in EPC (77.8%) and CIA (60%) samples compared with in HP (0%), TSA (6.6%), SSA/P (0%) and non-serrated adenoma (10%) samples (P<0.01). These findings demonstrated that there are different expression patterns between the serrated pathway and ACS, indicating that aberrant FHIT and inhibited COX-2 expression may be associated with serrated tumorigenesis. In addition, this data indicated that EPC may contain tumors derived from the serrated pathway as well as ACS.
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Affiliation(s)
- Akihiro Tamoto
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan
| | - Kazuo Yashima
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan
| | - Kohei Hosoda
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan
| | - Sohei Yamamoto
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan
| | - Soichiro Kawata
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan
| | - Yuichiro Ikebuchi
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan
| | - Kazuya Matsumoto
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan
| | - Koichiro Kawaguchi
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan
| | - Kenichi Harada
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan
| | - Yoshikazu Murawaki
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan
| | - Hajime Isomoto
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan
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Hanley MP, Hahn MA, Li AX, Wu X, Lin J, Wang J, Choi AH, Ouyang Z, Fong Y, Pfeifer GP, Devers TJ, Rosenberg DW. Genome-wide DNA methylation profiling reveals cancer-associated changes within early colonic neoplasia. Oncogene 2017; 36:5035-5044. [PMID: 28459462 PMCID: PMC5578878 DOI: 10.1038/onc.2017.130] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 03/04/2017] [Accepted: 03/14/2017] [Indexed: 12/15/2022]
Abstract
Colorectal cancer (CRC) is characterized by genome-wide alterations to DNA methylation that influence gene expression and genomic stability. Less is known about the extent to which methylation is disrupted in the earliest stages of CRC development. In this study we have combined laser-capture microdissection (LCM) with reduced representation bisulfite sequencing (RRBS) to identify cancer-associated DNA methylation changes in human aberrant crypt foci (ACF), the earliest putative precursor to CRC. Using this approach, methylation profiles have been generated for 10 KRAS-mutant ACF and 10 CRCs harboring a KRAS mutation, as well as matched samples of normal mucosa. Of 811 differentially methylated regions (DMRs) identified in ACF, 537 (66%) were hypermethylated and 274 (34%) were hypomethylated. DMRs located within intergenic regions were heavily enriched for AP-1 transcription factor binding sites and were frequently hypomethylated. Furthermore, gene ontology (GO) analysis demonstrated that DMRs associated with promoters were enriched for genes involved in intestinal development, including homeobox genes and targets of the Polycomb repressive complex 2 (PRC2). Consistent with their role in the earliest stages of colonic neoplasia, 75% of the loci harboring methylation changes in ACF were also altered in CRC samples, though the magnitude of change at these sites was lesser in ACF. While aberrant promoter methylation was associated with altered gene expression in CRC, this was not the case in ACF, suggesting the insufficiency of methylation changes to modulate gene expression in early colonic neoplasia. Together, these data demonstrate that DNA methylation changes, including significant hypermethylation, occur more frequently in early colonic neoplasia than previously believed, and identify epigenomic features of ACF that may provide new targets for cancer chemoprevention or lead to the development of new biomarkers for CRC risk.
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Affiliation(s)
- M P Hanley
- Center for Molecular Medicine, School of Medicine, UConn Health, Farmington, CT, USA.,Department of Genetics and Genome Sciences, UConn Health, Farmington, CT, USA
| | - M A Hahn
- Department of Surgery, City of Hope, Duarte, CA, USA
| | - A X Li
- Department of Information Sciences, City of Hope, Duarte, CA, USA
| | - X Wu
- Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - J Lin
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - J Wang
- Integrative Genomics Core, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - A H Choi
- Department of Surgery, City of Hope, Duarte, CA, USA
| | - Z Ouyang
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.,Institute for Systems Genomics, University of Connecticut, Farmington, CT, USA
| | - Y Fong
- Department of Surgery, City of Hope, Duarte, CA, USA
| | - G P Pfeifer
- Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI, USA
| | - T J Devers
- Division of Gastroenterology, School of Medicine, UConn Health, Farmington, CT, USA
| | - D W Rosenberg
- Center for Molecular Medicine, School of Medicine, UConn Health, Farmington, CT, USA.,Department of Genetics and Genome Sciences, UConn Health, Farmington, CT, USA.,Colon Cancer Prevention Program, Neag Comprehensive Cancer Center, UConn Health, Farmington, CT, USA
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24
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Okamoto K, Kitamura S, Kimura T, Nakagawa T, Sogabe M, Miyamoto H, Muguruma N, Takayama T. Clinicopathological characteristics of serrated polyps as precursors to colorectal cancer: Current status and management. J Gastroenterol Hepatol 2017; 32:358-367. [PMID: 27376251 DOI: 10.1111/jgh.13482] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/28/2016] [Indexed: 12/13/2022]
Abstract
Serrated polyps have long been thought to lack malignant potential in the human colorectum. However, identification of the serrated pathway to colorectal cancer based on molecular biology has improved our understanding of the pathogenesis of colorectal cancers. Accordingly, serrated polyps such as traditional serrated adenoma and sessile serrated adenoma/polyps (SSA/P) are now considered to be precursor lesions of the serrated pathway. Recently, serrated polyps were classified into three subtypes, consisting of hyperplastic polyp, SSA/P, and traditional serrated adenoma, according to the World Health Organization classification. It has been suggested that SSA/P in the proximal colon are a precursor lesion of pathogenesis of colorectal cancer and are characterized by BRAF mutation and a CpG island methylator phenotype with or without microsatellite instability. However, SSA/P is more challenging to detect by colonoscopy and is likely to account for some interval cancers, particularly in the proximal colon because it presents flat or sessile, isochroous appearance, and occasionally has a mucous cap. Furthermore, the possibility has been raised that pathologists misclassify SSA/P as hyperplastic polyp. It is important for gastroenterologists to recognize the endoscopic features of serrated polyps to facilitate their detection and removal and also to establish postpolypectomy surveillance guidelines. In this review, we discuss the recent classification of serrated polyps; the molecular characteristics of the serrated pathway; appropriate diagnostic methods using endoscopy, including a new image-enhanced endoscopic technique; and management of these lesions.
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Affiliation(s)
- Koichi Okamoto
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Shinji Kitamura
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Tetsuo Kimura
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Tadahiko Nakagawa
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Masahiro Sogabe
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Naoki Muguruma
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
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DNA Methylation Identifies Loci Distinguishing Hereditary Nonpolyposis Colorectal Cancer Without Germ-Line MLH1/MSH2 Mutation from Sporadic Colorectal Cancer. Clin Transl Gastroenterol 2016; 7:e208. [PMID: 27977020 PMCID: PMC5288582 DOI: 10.1038/ctg.2016.59] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 10/26/2016] [Indexed: 12/26/2022] Open
Abstract
Objectives: Roughly half of hereditary nonpolyposis colorectal cancer (HNPCC) cases are Lynch syndrome and exhibit germ-line mutations in DNA mismatch repair (MMR) genes; the other half are familial colorectal cancer (CRC) type X (FCCTX) and are MMR proficient. About 70% of Lynch syndrome tumors have germ-line MLH1 or MSH2 mutations. The clinical presentation, histopathological features, and carcinogenesis of FCCTX resemble those of sporadic MMR-proficient colorectal tumors. It is of interest to obtain biomarkers that distinguish FCCTX from sporadic microsatellite stable (MSS) CRC, to develop preventive strategies. Methods: The tumors and adjacent normal tissues of 40 patients with HNPCC were assayed using the Illumina Infinium HumanMethylation27 (HM27) BeadChip to assess the DNA methylation level at about 27,000 loci. The germ-line mutation status of MLH1 and MSH2 and the microsatellite instability status in these patients were obtained. Genome-wide DNA methylation measurements of three groups of patients with general CRC were downloaded from public domain databases. Probes with DNA methylation levels that differed significantly between patients with sporadic MSS CRC and FCCTX were examined, to explore their potential as biomarkers. Results: We found that MSS HNPCC tumors were overwhelmingly hypomethylated compared with those from patient groups with other types of CRC, including germ-line MLH1/MSH2-mutated HNPCC and sporadic MSS CRC. Five gene-marker panels that exhibited a sensitivity of 100% and a specificity higher than 90% in both discovery and validation cohorts were proposed to distinguish MSS HNPCC tumors from sporadic MSS CRC. Conclusions: Our results warrant further investigation and validation. The loci identified here may become useful biomarkers for distinguishing between FCCTX and sporadic MSS CRC tumors.
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Cao HL, Dong WX, Xu MQ, Zhang YJ, Wang SN, Piao MY, Cao XC, Wang BM. Clinical features of upper gastrointestinal serrated lesions: An endoscopy database analysis of 98746 patients. World J Gastroenterol 2016; 22:10038-10044. [PMID: 28018111 PMCID: PMC5143750 DOI: 10.3748/wjg.v22.i45.10038] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 11/03/2016] [Accepted: 11/16/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To analyse the clinical features of patients with the serrated lesions in the upper gastrointestinal tract (UPGI) tract.
METHODS Patients who underwent routine esophagogastroduodenoscopy (EGD) at the Digestive Endoscopy Centre of General Hospital, Tianjin Medical University between January 2011 and December 2015 were consecutively recruited. Patients with UPGI serrated lesions were consecutively identified. The patients’ demographics and histopathology were recorded. The colorectal findings for patients who underwent colonoscopy simultaneously or within six months were also extracted from the colonoscopy database. In addition, we analysed differences in colorectal neoplasia detection between the study patients and randomly selected patients matched for age and gender who did not exhibit serrated lesions and who also underwent colonoscopy in the same period.
RESULTS A total of 21 patients out of 98746 patients (0.02%) who underwent EGD were confirmed to have serrated lesions with predominantly crenated, sawtooth-like configurations. The mean age of the 21 patients was (55.3 ± 17.2) years, and 11 patients were male (52.4%). In terms of the locations of the serrated lesions, 17 were found in the stomach (including 3 in the cardia, 9 in the corpus and 5 in the antrum), 3 were found in the duodenum, and 1 was found in the esophagus. Serrated lesions were found in different mucosal lesions, with 14 lesions were detected in polyps (8 hyperplastic polyps and 6 serrated adenomas with low grade dysplasia), 3 detected in Ménétrier gastropathy, 3 detected in an area of inflammation or ulcer, and 1 detected in the intramucosal carcinoma of the duodenum. In addition, colonoscopy data were available for 18 patients, and a significantly higher colorectal adenoma detection rate was observed in the UPGI serrated lesions group than in the randomly selected age- and gender-matched group without serrated lesions who also underwent colonoscopy in the same period (38.9% vs 11.1%, OR = 5.091, 95%CI: 1.534-16.890, P = 0.010). The detection rate of advanced adenoma was also higher in the UPGI serrated lesions group (22.2% vs 4.2%, OR = 6.571, 95%CI: 1.322-32.660, P = 0.028).
CONCLUSION Serrated lesions in the UPGI were detected in various mucosal lesions with different pathological morphologies. Moreover colonoscopy is recommended for the detection of concurrent colorectal adenoma for these patients.
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Mo A, Jackson S, Varma K, Carpino A, Giardina C, Devers TJ, Rosenberg DW. Distinct Transcriptional Changes and Epithelial-Stromal Interactions Are Altered in Early-Stage Colon Cancer Development. Mol Cancer Res 2016; 14:795-804. [PMID: 27353028 DOI: 10.1158/1541-7786.mcr-16-0156] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 06/11/2016] [Indexed: 12/11/2022]
Abstract
UNLABELLED Although the progression of mutated colonic cells is dependent upon interactions between the initiated epithelium and surrounding stroma, the nature of these interactions is poorly understood. Here, the development of an ultrasensitive laser capture microdissection (LCM)/RNA-seq approach for studying the epithelial and stromal compartments of aberrant crypt foci (ACF) is described. ACF are the earliest identifiable preneoplastic lesion found within the human colon and are detected using high-definition endoscopy with contrast dye spray. The current analysis focused on the epithelium of ACF with somatic mutations to either KRAS, BRAF, or APC, and expression patterns compared with normal mucosa from each patient. By comparing gene expression patterns among groups, an increase in a number of proinflammatory NF-κB target genes was identified that was specific to ACF epithelium, including TIMP1, RELA, and RELB Distinct transcriptional changes associated with each somatic mutation were observed and a subset of ACF display BRAF(V600E)-mediated senescence-associated transcriptome characterized by increased expression of CDKN2A Finally, LCM-captured ACF-associated stroma was found to be transcriptionally distinct from normal-appearing stroma, with an upregulation of genes related to immune cell infiltration and fibroblast activation. Immunofluorescence confirmed increased CD3(+) T cells within the stromal microenvironment of ACF and an abundance of activated fibroblasts. Collectively, these results provide new insight into the cellular interplay that occurs at the earliest stages of colonic neoplasia, highlighting the important role of NF-κB, activated stromal fibroblasts, and lymphocyte infiltration. IMPLICATIONS Fibroblasts and immune cells in the stromal microenvironment play an important role during the earliest stages of colon carcinogenesis. Mol Cancer Res; 14(9); 795-804. ©2016 AACR.
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Affiliation(s)
- Allen Mo
- Center for Molecular Medicine, School of Medicine, UConn Health, Farmington, Connecticut. Colon Cancer Prevention Program, Neag Comprehensive Cancer Center, School of Medicine, UConn Health, Farmington, Connecticut
| | | | - Kamini Varma
- Thermo Fisher Scientific, South San Francisco, California
| | - Alan Carpino
- Thermo Fisher Scientific, South San Francisco, California
| | - Charles Giardina
- Department of Molecular & Cell Biology, University of Connecticut, Storrs, Connecticut
| | - Thomas J Devers
- Division of Gastroenterology, School of Medicine, UConn Health, Farmington, Connecticut
| | - Daniel W Rosenberg
- Center for Molecular Medicine, School of Medicine, UConn Health, Farmington, Connecticut. Colon Cancer Prevention Program, Neag Comprehensive Cancer Center, School of Medicine, UConn Health, Farmington, Connecticut.
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Rau TT, Atreya R, Aust D, Baretton G, Eck M, Erlenbach-Wünsch K, Hartmann A, Lugli A, Stöhr R, Vieth M, Wirsing AM, Zlobec I, Katzenberger T. Inflammatory response in serrated precursor lesions of the colon classified according to WHO entities, clinical parameters and phenotype-genotype correlation. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2016; 2:113-24. [PMID: 27499921 PMCID: PMC4907061 DOI: 10.1002/cjp2.41] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 01/23/2016] [Indexed: 12/14/2022]
Abstract
Studies on traditional serrated adenoma (TSA) and sessile serrated adenoma with dysplasia (SSA‐D) are rare due to the low frequency of these lesions, which are well defined by the latest WHO classification. However, introducing new morphological criteria such as intra‐epithelial lymphocytes (IELs) might facilitate colorectal polyp diagnoses. Additionally, the phenotype–genotype correlation needs to be updated as the terminology has repeatedly changed. This study analysed 516 polyps, consisting of 118 classical adenomas (CAD), 116 hyperplastic polyps (HPP), 179 SSAs, 41 SSA‐Ds, and 62 TSAs. The lesions were analysed in relation to the patients’ clinical parameters including gender, age, localisation, and size. The inflammatory background of the polyps was quantified and BRAF and KRAS mutations as well as MLH1 and CDKN2A promoter methylation were assessed. In multivariate analyses, an increase in IELs was an independent and robust new criterion for the diagnosis of SSA‐D (p < 0.001). Superficial erosions and acute neutrophil granulocytes led to reactive changes potentially resembling dysplasia. KRAS and BRAF mutations were associated with CAD/TSA and HPP/SSA, respectively. However, almost half of TSAs had a BRAF mutation and were KRAS wild type. CDKN2A seems to precede MLH1 hyper‐methylation within the serrated carcinogenesis model. The genotyping of WHO‐based entities – and especially SSA – has sharpened in comparison to previously published data. TSAs can be sub‐grouped according to their mutation status. Of note, the higher number of IELs in SSA‐D reflects their close relationship to colorectal cancers with micro‐satellite instability. Therefore, IELs might represent a new diagnostic tool for SSA‐D.
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Affiliation(s)
- Tilman T Rau
- Institute of Pathology, University Bern, BernSwitzerland; Institute of Pathology, Friedrich-Alexander University Erlangen-NurembergErlangenGermany
| | - Raja Atreya
- Medical Clinic 1, Friedrich-Alexander University Erlangen-Nuremberg Erlangen Germany
| | - Daniela Aust
- Institute of Pathology, University Hospital Dresden Carl Gustav Carus Dresden Germany
| | - Gustavo Baretton
- Institute of Pathology, University Hospital Dresden Carl Gustav Carus Dresden Germany
| | - Matthias Eck
- Institute of Pathology, Hospital Aschaffenburg Aschaffenburg Germany
| | | | - Arndt Hartmann
- Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg Erlangen Germany
| | | | - Robert Stöhr
- Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg Erlangen Germany
| | - Michael Vieth
- Institute of Pathology, Hospital Bayreuth Bayreuth Germany
| | - Anna M Wirsing
- Institute of Pathology, Friedrich-Alexander University Erlangen-NurembergErlangenGermany; Department of Medical Biology, Faculty of Health SciencesUniversity of TromsøTromsøNorway
| | - Inti Zlobec
- Institute of Pathology, University Bern, Bern Switzerland
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Genomic-Wide Analysis with Microarrays in Human Oncology. MICROARRAYS 2015; 4:454-73. [PMID: 27600234 PMCID: PMC4996403 DOI: 10.3390/microarrays4040454] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Revised: 10/08/2015] [Accepted: 10/13/2015] [Indexed: 12/19/2022]
Abstract
DNA microarray technologies have advanced rapidly and had a profound impact on examining gene expression on a genomic scale in research. This review discusses the history and development of microarray and DNA chip devices, and specific microarrays are described along with their methods and applications. In particular, microarrays have detected many novel cancer-related genes by comparing cancer tissues and non-cancerous tissues in oncological research. Recently, new methods have been in development, such as the double-combination array and triple-combination array, which allow more effective analysis of gene expression and epigenetic changes. Analysis of gene expression alterations in precancerous regions compared with normal regions and array analysis in drug-resistance cancer tissues are also successfully performed. Compared with next-generation sequencing, a similar method of genome analysis, several important differences distinguish these techniques and their applications. Development of novel microarray technologies is expected to contribute to further cancer research.
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The molecular pathogenesis of colorectal cancer and its potential application to colorectal cancer screening. Dig Dis Sci 2015; 60:762-72. [PMID: 25492499 PMCID: PMC4779895 DOI: 10.1007/s10620-014-3444-4] [Citation(s) in RCA: 112] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Accepted: 11/15/2014] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Advances in our understanding of the molecular genetics and epigenetics of colorectal cancer have led to novel insights into the pathogenesis of this common cancer. These advances have revealed that there are molecular subtypes of colon polyps and colon cancer and that these molecular subclasses have unique and discrete clinical and pathological features. Although the molecular characterization of these subgroups of colorectal polyps and cancer is only partially understood at this time, it does appear likely that classifying colon polyps and cancers based on their genomic instability and/or epigenomic instability status will eventually be useful for informing approaches for the prevention and early detection of colon polyps and colorectal cancer. CONCLUSIONS In this review, we will discuss our current understanding of the molecular pathogenesis of the polyp to cancer sequence and the potential to use this information to direct screening and prevention programs.
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